OAT

protein-coding

ornithine aminotransferase

Gene summary

This gene encodes the mitochondrial enzyme ornithine aminotransferase, which is a key enzyme in the pathway that converts arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Mutations that result in a deficiency of this enzyme cause the autosomal recessive eye disease Gyrate Atrophy. Alternatively spliced transcript variants encoding different isoforms have been described. Related pseudogenes have been defined on the X chromosome. [provided by RefSeq, Jan 2010]

MANE transcript

NM_000274.4

Inheritance

ClinVar variants

P:168U:187B:192

Top phenotype

Gyrate atrophy of choroid and retina

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr10:124,397,303-124,418,976

External References & Databases

Ensembl (ENSG00000065154)

Transcript & Mutation Effects

hg38 • Region Span ~21.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ornithine aminotransferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009796

Submitter: PanelApp Australia

ornithine aminotransferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009796

Submitter: ClinGen

The relationship between OAT and gyrate atrophy of the choroid and retina, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 2, 2019. OAT encodes ornithine aminotransferase, a mitochondrial enzyme that catalyzes the pyridoxal 5′-phosphate-dependent transformation of L-ornithine to L-glutamate 5-semialdehyde, which spontaneously forms pyrroline-5-carboxylate. Variants in OAT causing gyrate atrophy were first reported in 1988 (Ramesh et al, PMID 3375240; Mitchel et al, PMID 3339136). Hyperornithininemia is a consistent biochemical finding in these patients. Data from 10 patients with 13 unique variants (missense, nonsense, frameshift, splicing, large deletion) from 6 publications were curated (Mitchel et al, 1988, PMID 3339136; Ramesh et al, 1988, PMID 3375240; Mitchel et al, 1989, PMID 2492100; Mashima et al, 1992, PMID 1609808; Doimo et al, 2013, PMID 23076989; Katagiri et al, 2014, PMID 24429551). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. Of note, rare individuals with OAT deficiency have been reported who presented with hyperammonemia and low ornithine in the neonatal period, later developing hyperornithinemia (Cleary et al, 2005, PMID 16151897; Zubarioglu et al, 2016; PMID 27037922). While these individuals had no signs of gyrate atrophy, it is possible that it may develop later in life. The relationship between OAT and gyrate atrophy is supported by extensive experimental evidence including the biochemical function of ornithine aminotransferase, which is consistent with the biochemical features of the disease (Juncosa et al, 2103, PMID 23747282), expression of OAT in the retina (Bernstein et al, 1988, PMID 9815288), functional studies in patient and non-patient cells (Heinänen et al, 1988, PMID 9727717; Montioli et al, 2018, PMID 30251682), as well as the phenotype in naturally-occurring and knock-out mouse models (Bisaillon et al, 2014, PMID 25264521; Wang et al, 1995, PMID 7550347; Wang et al, 2000, PMID 10655512). In summary, OAT is definitively associated with gyrate atrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.

ornithine aminotransferase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009796

Submitter: Orphanet

ornithine aminotransferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009796

Submitter: Labcorp Genetics (formerly Invitae)

ornithine aminotransferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009796

Submitter: Natera

ornithine aminotransferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009796

Submitter: G2P

Clinical Genomic Database (CGD)

Gyrate atrophy of choroid and retinaAR

Manifestation: Biochemical; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Dietary management (eg, with arginine restriction) may be beneficial

Refs: 4122112; 572946; 7444439; 7356686; 3339136; 1737786; 11831916; 10604138; 110617919; 1297489; 15750329; 22674428; 34340878

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OAT variants in ClinVar

12 Conditions Cataloged

Ornithine aminotransferase deficiencyTotal: 629

Inborn genetic diseasesTotal: 62

not providedTotal: 36

HyperornithinemiaTotal: 15

Retinal dystrophyTotal: 11

not specifiedTotal: 9

OAT-related disorderTotal: 8

Gyrate atrophy of choroid and retina with pyridoxine-responsive ornithinemiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000274.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	5 clinvar	183 clinvar		189
missense	10 clinvar	35 clinvar	179 clinvar	8 clinvar	1 clinvar	233
nonsense	13 clinvar	19 clinvar	1 clinvar			33
start loss	3 clinvar	1 clinvar				4
frameshift	22 clinvar	34 clinvar				56
splice donor/acceptor (+/-2bp)	6 clinvar	24 clinvar	2 clinvar			32
Total	54	114	187	191	1	547

Highest pathogenic variant AF is 0.000119590986

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 79 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000274.4	RefSeq	NP_000265.1	9	MANE Select
ENST00000368845.6	Ensembl	ENSP00000357838.5	9	MANE Select
NM_001171814.2	RefSeq	NP_001165285.1	8	Standard
NM_001322965.2	RefSeq	NP_001309894.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Hyperornithinemia with gyrate atrophy (HOGA)
Creatine deficiency, guanidinoacetate methyltransferase deficiency
L-arginine:glycine amidinotransferase deficiency
Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome]

Biological Process

visual perception
cellular amino acid biosynthetic process
arginine catabolic process to proline via ornithine
arginine catabolic process to glutamate
protein hexamerization

Molecular Function

ornithine-oxo-acid transaminase activity
pyridoxal phosphate binding

Cellular Component

nucleoplasm
cytoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368845
Coding exons: 9
Length: 21674
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.876	204	242	0.842	0.0000129	2848
Missense (PolyPhen)		63	92.108	0.68398		1129
Synonymous	1.01	81	93.4	0.867	0.00000563	882
Loss of Function	1.70	13	21.5	0.605	0.00000121	249

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:258870]: A disorder clinically characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. Characteristic chorioretinal atrophy with progressive constriction of the visual fields leads to blindness at the latest during the sixth decade of life. Patients generally have normal intelligence. {ECO:0000269|PubMed:1612597, ECO:0000269|PubMed:1737786, ECO:0000269|PubMed:23076989, ECO:0000269|PubMed:2793865, ECO:0000269|PubMed:3375240, ECO:0000269|PubMed:7668253, ECO:0000269|PubMed:7887415}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.642

Intolerance Scores

LoFtool: 0.0996
RVIS EVS: -0.76
RVIS percentile EVS: 13.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.977

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium